The pyridine C-nucleoside having the structure: ##STR2## which is isosteric to nicotinamide riboside, was synthesized by these inventors [Kabat, Pankiewicz, Watanabe, J. Med. Chem., 1987, 30, 924-927; Kabat et al., Chem. Pharm. Bull., 1988, 36, 634-640; Pankiewicz et al., J. Org. Chem., 1988, 53, 3473-3479] in the hope that such an analogue may be converted biologically into the corresponding nicotinamide adenine dinucleotide, NAD coenzyme, analog having the structure: ##STR3## and exert biological activities. The non-charged NAD isostere (2), which is incapable of participating in biological oxidation-reduction process(es) may inhibit the NAD-dependent enzyme, IMP-dehydrogenase, and may induce anticancer activity by blocking the de novo GMP synthesis.
The NAD analog (2) which contains the C-nucleoside (1), was found to be a general competitive inhibitor (with respect to NAD) of various dehydrogenases such as inosine monophosphate dehydrogenase (IMPDH), glutamate dehydrogenase (GDH), lactate dehydrogenase (LDH) and malate dehydrogenase (MDH). Interestingly, the NAD analogue (2) exhibited highly potent and selective inhibitory activity against alcohol dehydrogenase from horse liver.
The present invention relates to the novel class of NAD analogs which contain the nicotinamide, picolinamide or isonicotinamide C-nucleoside in place of nicotinamide riboside. The compounds of this invention have the pyrophosphate (--P--O--P--) bridge connecting the nucleosides or, alternatively, can have a methylene diphosphonate (--P--CH.sub.2 --P--), or difluoromethylene diphosphonate (--P--CF.sub.2 --P--) group as the bridge.
Analogues that contain a methylene diphosphonate (--P--CH.sub.2 --P--) or difluoromethylene diphosphonate (--P--CF.sub.2 --P--) group in place of the pyrophosphate (--P--O--P--) bridge are resistant to enzymic hydrolysis to their corresponding nucleoside 5'-monophosphates. The 2'-fluoroinated adenosine analogues cannot be converted into the corresponding NADP analogues. Such analogues, therefore, cannot interfere with NADP dependent enzymes. In addition, fluorine substituted NAD analogues, as more lipophilic than their corresponding hydroxyl or pyrophosphate groups containing counterparts, could penetrate biological membranes and may better fit to the hydrophobic binding pocket of dehydrogenases.
The compositions of this invention are useful as potent inhibitors of various dehydrogenases of eucaryotic and procaryotic origin. These compounds may also be utilized as therapeutic agents exhibiting anticancer and antiviral activity.